Seasonal and universal Vaccination in aged populations with pre-existing immunity

项目摘要 目前基于高变血凝素（HA）蛋白的流感疫苗接种未能提供 有效的交叉保护。接种疫苗的有效性在老年人群中很低，即使预先存在 免疫力预先存在的免疫力对普适性和季节性疫苗免疫原性和有效性的影响 接种疫苗在老年人中基本上仍然没有得到很好的理解。开发新的流感疫苗， 疫苗接种策略提高了年轻初治宿主和老年宿主的交叉保护效力， 豁免权是最高优先事项。在未处理动物中检测的诱导交叉保护的单一保守抗原靶标 包括甲型流感病毒M2细胞外结构域（M2 e）、HA-茎结构域和神经氨酸酶（NA）的模型， 报告，但不足以翻译给人类。初治和老年宿主中的多靶点通用疫苗 已经存在免疫力的人还有待开发。 我们开发了M2 e的异源串联重复序列（5xM 2 e），其呈递在免疫原性病毒样 颗粒（5xM 2 e VLP）。用5xM 2 e VLP疫苗接种有效地扩大了交叉保护， 次优应开发进一步改进的通用疫苗。我们的初步研究发现 通过M2 e和NA免疫提高交叉保护的协同效应。因此，作为一个新的普遍 作为疫苗候选，我们开发了含有多亚型NA和5xM 2 e的多NA +5xM 2 e VLP疫苗， 相同的VLP粒子此外，我们新设计了遗传连锁的新型重组M2 e-stalk 有效诱导M2 e和HA-茎免疫并赋予广泛交叉免疫的通用蛋白疫苗， 群体保护。佐剂通用疫苗接种将克服衰老相关的免疫衰老， 激活初始宿主或已存在免疫力的老年人群中的T和B免疫细胞。 在这个项目中，我们将测试新的通用疫苗接种诱导多重免疫（M2 e， Stalk，NA）将增强交叉保护在患有或 没有预先存在的豁免权。在目标1下，我们将确定多靶点通用疫苗在 在幼稚和预先存在的免疫条件下的年轻成年小鼠和雪貂。在目标2研究中，我们将 通过多靶点新通用疫苗确定交叉保护性免疫的持久性，并测试a 在老龄小鼠和雪貂动物模型中增强交叉保护的疫苗接种策略。在Aim 3中，我们将 青、老年人多靶点普免交叉保护性免疫机制探讨 小鼠模型。本项目的研究成果在翻译科学方面具有重要意义， 提高流感疫苗交叉保护效力的相关性。

PROJECT SUMMARY Current influenza (flu) vaccination based on hypervariable hemagglutinin (HA) protein fails to provide effective cross protection. The efficacy of vaccination is low in the aged populations even with pre-existing immunity. The impacts of pre-existing immunity on the immunogenicity and efficacy of universal and seasonal vaccination largely remain not well understood in the aged populations. Development of new flu vaccines and vaccination strategies improving cross protective efficacy in young naïve and aged hosts with pre-existing immunity is of high priority. Mono conserved antigenic targets inducing cross protection tested in naïve animal models include the flu A virus M2 extracellular domain (M2e), HA-stalk domains, and neuraminidase (NA) were reported but insufficient for translation to humans. The multi-target universal vaccines in naïve and aged hosts with pre-existing immunity remain to be developed. We developed heterologous tandem repeat of M2e (5xM2e) presented on immunogenic virus-like particles (5xM2e VLP). Vaccination with 5xM2e VLP was effective in broadening cross protection but suboptimal. A further improved universal vaccine should be developed. Our preliminary studies found synergistic effects on improving cross protection by both M2e and NA immunity. Therefore, as a new universal vaccine candidate, we developed a multi NA + 5xM2e VLP vaccine containing multi-subtype NA and 5xM2e on the same VLP particle. In addition, we newly designed genetically linked novel recombinant M2e-stalk universal protein vaccines effectively inducing both M2e and HA-stalk immunity and conferring broad cross- group protection. Adjuvanted universal vaccination will overcome the aging-related immune senescence by activating T and B immune cells in naïve hosts or aged populations under pre-existing immunity. In this project, we will test the hypothesis that new universal vaccination inducing multi immunity (M2e, Stalk, NA) will enhance the breadth and efficacy of cross protection in adult and aged populations with or without pre-existing immunity. Under Aim 1, we will determine the efficacy of multi-target universal vaccines in young adult mice and ferrets under naïve and pre-existing immune conditions. In Aim 2 studies, we will determine the durability of cross protective immunity by multi targeting new universal vaccines and test a vaccination strategy enhancing cross protection in aged mouse and ferret animal models. In the Aim 3, we will investigate cross protective immune mechanisms of multi targeting universal vaccination in young and aged mouse models. The outcomes in this project will be highly significant in the aspect of translational science and relevance to improve the cross protective efficacy of flu vaccination.